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Summary: Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within‐trial biases in meta‐analysis include the use of empirical evidence from an external collection of meta‐analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta‐analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples. [ABSTRACT FROM AUTHOR]

Background Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting The study was set in primary and secondary care in England from 2010 to 2017. Participants Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval –£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval –£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration This trial is registered as ISRCTN76607611. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information. Plain language summary People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients’ attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks. Scientific summary Background Dual antiplatelet therapy (DAPT), a combination of aspirin and clopidogrel, prasugrel or ticagrelor, is recommended for up to 12 months for secondary prevention of ischaemic events (heart attack and stroke) among people undergoing coronary interventions [coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI)] and people with acute coronary syndrome (ACS) who are medically managed. Randomised controlled trials (RCTs) in these populations suggest that DAPT increases the risk of bleeding compared with aspirin monotherapy, and that more potent DAPT (with prasugrel and ticagrelor) increases the risk of bleeding compared with less potent DAPT (with clopidogrel). Adding an anticoagulant to DAPT (e.g. for the management of atrial fibrillation), known as triple therapy (TT), increases risk further. ‘Real-world’ bleeding among populations exposed to different DAPT and TT regimens has not been previously quantified. The economic impact of bleeding events is poorly characterised, in particular for minor bleeding, as is their impact on health-related quality of life (HRQoL). Objectives 1.Estimate rates of major and minor bleeding events with different DAPT (and TT) exposures among CABG, PCI and conservatively treated ACS patients. 2.Estimate hazard ratios (HRs) for bleeding for different antiplatelet regimens: for the PCI cohort, we compared aspirin and clopidogrel (AC) with aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); for the CABG and ACS no-procedure cohorts, we compared aspirin with AC. 3.Review the literature to estimate the deterioration in utility (quality-adjusted life-years) of patients who have minor or major bleeding events. 4.Revise/extend existing economic models of the cost-effectiveness of different DAPT regimens to include estimates of the incidence of minor and major bleeding events and associated impacts on utility in the general population. 5.Estimate the resources required and associated costs incurred of treating major and minor events of the alternative DAPT (TT) exposures in the three specified patient populations. 6.Understand patients’ perspectives of DAPT, and the factors that influence responses to nuisance bleeding focusing on adherence and information-seeking (this objective was identified through the patient and public involvement work after the start of the ADAPTT study). Methods Objectives 1 and 2 We conducted a study to identify confounders systematically by performing a systematic review of RCTs and cohort studies; conducting semistructured interviews with six cardiac surgeons, six cardiologists and five general practitioners (GPs); and conducting a survey of 79 cardiologists and 31 cardiac surgeons. We used linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations (CABG, PCI and conservatively managed ACS patients) eligible for three ‘target trials’. Inclusion criteria for the target trial were as follows: ≥ 18 years of age, ≥ 1 year of data in CPRD before the index event, no prescription for DAPT or anticoagulants in the preceding 3 months and a prescription for aspirin or DAPT within 2 months of discharge after the index event. The primary outcome was any bleeding event (CPRD or HES data) up to 12 months after the index event. We described rates of bleeding among patients prescribed different DAPT regimens and TT. We estimated adjusted HRs for time to first bleed comparing DAPT with AC (reference) versus aspirin monotherapy for CABG and conservatively managed ACS patient, and, in the emergency PCI population, DAPT with prasugrel versus DAPT with clopidogrel for ST-elevation myocardial infarction (STEMI) patients only and DAPT with ticagrelor versus DAPT with clopidogrel for all the emergency PCI population. We prespecified five sensitivity analyses and conducted three: sensitivity analysis 1 – multiple imputation for eligible patients for whom we had no data to assign an intervention; sensitivity analysis 3 – restricted to patients at low risk of bleeding; and sensitivity analysis 4 – repeating primary outcome analysis without censoring of any CPRD or HES bleed events at transfer-out or last collection date. The transfer-out or last collection date reflect the date that a patient leaves the general practice or the date that the last capture from CPRD was made. Objective 3 A systematic review was conducted of primary research and decision-analytic modelling studies reporting utility decrements for bleeds related to DAPT through a search of MEDLINE, PubMed and references of included studies. A health elicitation study was undertaken, comprising 21 participants (PCI, CABG and conservatively managed ACS) who completed an elicitation exercise involving vignettes describing minor and major bleeds and the EuroQol-5 Dimensions, three-level version (EQ-5D-3L), and the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Utility decrements were derived using linear regression, and were compared with existing estimates. Objective 4 No formal cost-effectiveness evaluation was undertaken. Objective 5 Data on health-care use were derived from the linked CPRD–HES data set. The total health-care costs associated with the different antiplatelet regimens in the three target trials were measured at 1, 2 and 3 years after the start of follow-up. We used inverse probability of treatment weighting to adjust for the same confounders identified for the main ADAPTT analysis. The total health-care costs at 1, 2 and 3 years of follow-up were estimated by fitting weighted generalised linear models with gamma distribution and log-link. Objective 6 Two focus groups were conducted with patients at the early stages of treatment (0–3 months, nine participants), and two with patients coming to the end of treatment (9–12 months, 12 participants), to explore their experiences with DAPT. Recordings were transcribed verbatim, anonymised and analysed using framework analysis. Research findings Objectives 1 and 2 Confounders study A total of 70 potential confounders were identified by systematic review, clinician interviews and surveys; of these, 34 (49%) were classified as true confounders (factors that influence both the assigned intervention and the outcome), of which 31 (91%) were identified by systematic review and three (9%) by clinician interview, and 31 (91%) were confirmed by the survey. The clinician interviews identified hard-to-measure factors not identified in the review (drug potency, resistance to antiplatelet medication and clinician concerns about adherence). Data that would enable the characterisation of risk, including presentation risk and procedural risk factors, were unavailable for 17 of the 34 confounders (50%). The ADAPTT study A proportion of eligible participants were excluded from each target trial because they could not be assigned an intervention at baseline (17%, 40% and 9% of the CABG, conservatively managed ACS and emergency PCI patients, respectively). The incidence of any bleeding was 5%, 10% and 9% in CABG patients, conservatively managed ACS patients and emergency PCI patients, respectively; the corresponding rates of minor bleeding were 4%, 7% and 7%, respectively. Compared with aspirin monotherapy, DAPT was associated with an increase in the hazards of any bleeding and of major adverse cardiovascular events (MACEs) among CABG [HR 1.72, 95% confidence interval (CI) 1.15 to 2.57, and HR 2.06, 95% CI 1.23 to 3.46, respectively] and conservatively managed ACS patients (HR 1.43, 95% CI 1.21 to 1.69, and HR 1.57, 95% CI 1.38 to 1.78, respectively). Among emergency PCI patients, compared with less potent DAPT (with clopidogrel), more potent DAPT with ticagrelor (ACS and STEMI patients only) or prasugrel (STEMI patients only) increased the hazard of bleeding (HR 1.47, 95% CI 1.19 to 1.82; HR 1.47, 95% CI 1.08 to 2.00; and HR 1.77, 95% CI 1.21 to 2.58, respectively), but there was no association with MACEs (HR 1.06, 95% CI 0.89 to 1.27; HR 1.21, 95% CI 0.94 to 1.56; and HR 1.10, 95% CI 0.80 to 1.51, respectively). Sensitivity analyses using multiple imputation to impute for the intervention assigned at baseline did not materially change these results. Non-adherence to the treatment assigned at baseline was generally higher in the CABG and conservatively-managed ACS target trials (affecting up to 46% and 44% of patients, respectively) than in the in emergency PCI (affecting up to 33% of patients). Triple therapy The median duration of TT was 3.5 months. The incidence of any bleeding among patients prescribed TT was 18%. There was no difference in the incidence of any bleeding, or of major bleeding or minor bleeding, between patients on TT with warfarin and patients on TT with a non-vitamin K oral anticoagulant (NOAC). However, mortality from bleeding was higher among patients on TT with a NOAC than among patients on TT with warfarin (2% vs. 0%), as was the incidence of stroke (4% vs. 0%). Objective 3 Twelve eligible studies were included for review. Reported utility decrements ranged from –0.002 to –0.03 for minor bleeds and –0.007 to –0.05 for major bleeds. Data sources used to estimate the decrements lacked relevance to our population group, and few studies adequately reported details of their measurement and valuation approaches. Our patient health elicitation study elicited utility decrements that overlapped existing estimates, ranging from –0.000848 to –0.00828 for minor bleeds and from –0.0187 to –0.0621 for major bleeds. However, the magnitude of difference depended on the instrument (EQ-5D-5L or EQ-5D-3L), estimation method and valuation approach applied. Objective 5 The mean total health-care cost in the year prior to the index event was much higher for CABG patients (£13,601) than for conservatively managed ACS (£3528) or emergency PCI patients (£3625). For CABG patients, mean costs were similar between different antiplatelet regimens (£13,623 for aspirin monotherapy and £13,537 for DAPT with clopidogrel). For conservatively managed ACS, patients on DAPT with clopidogrel had a lower mean total health-care cost in the year prior to the index date than patients on aspirin monotherapy (£3317 vs. £3857, respectively). Among emergency PCI patients, those initiated on DAPT with clopidogrel had a higher mean total health-care cost in the year prior to the index event (£4492) than those initiated on DAPT with prasugrel (STEMI patients only) (£1660) or ticagrelor (£2829). Among the CABG population, there was no difference in mean cumulative health-care costs between initiation of DAPT with clopidogrel and initiation of aspirin monotherapy; the mean difference at 1, 2 and 3 years was £94 (95% CI –£555 to £763), £236 (95% CI –£831 to £1223) and £113 (95% CI –£1318 to £1102), respectively. Among the conservatively managed ACS population, the mean cumulative health-care costs were estimated to be slightly higher if all patients were treated with DAPT with clopidogrel than if all were treated with aspirin monotherapy; the mean difference at 1, 2 and 3 years was £610 (95% CI –£626 to £1516), £1118 (95% CI –£226 to £2206) and £1225 (95% CI –£426 to £2423), respectively, although there was considerable overlap between CIs. For emergency PCI patients, the estimated cumulative health-care costs were comparable under the different antiplatelet regimens among patients not receiving concurrent proton pump inhibitor (PPI) prescriptions, but were higher for patients receiving DAPT with ticagrelor than for patients receiving DAPT with clopidogrel. At 1 year, for example, the predicted mean difference in health-care costs if all patients received DAPT with ticagrelor rather than DAPT with clopidogrel was £72 (95% CI –£532 to £762) among those not receiving concurrent PPI therapy and £1145 (95% CI £269 to £2195) among those receiving concurrent PPI therapy. Among STEMI patients receiving concurrent PPI therapy, DAPT with prasugrel was associated with higher costs than DAPT with clopidogrel or DAPT with ticagrelor. Objective 6 Participants would adhere to DAPT when they believed that DAPT was important to ACS outcomes. Those who had experienced nuisance bleeding reported symptoms to be mild and manageable and did not report the bleed to their GP. Adherence was influenced by participants’ and their families’ understanding of the risks and benefits of DAPT, and their ability to manage symptoms. Factors influencing knowledge about DAPT included access to medication counselling; processing of and engaging with information communicated during medication counselling; and access to timely, relevant and expert information and advice after discharge from hospital. Conclusions There is underascertainment of minor/nuisance bleeding in the CPRD, probably as a result of under-reporting of nuisance bleeding by patients to their GPs. In three retrospective population-based cohort studies emulating target trials, there was an increased risk of bleeding among patients receiving DAPT compared with those receiving aspirin monotherapy (CABG and conservatively managed ACS patients) and among patients receiving more potent DAPT than among those receiving less potent DAPT (emergency PCI patients), but not the expected decrease in MACEs. We identified several potential biases that may have influenced the results of the ADAPTT study as a result of imperfect emulation of the defined target trials: (1) selection bias – we excluded a subgroup of the eligible population because they could not be assigned an intervention; (2) confounding – we had no data for half of the confounders identified, including procedure-related characteristics and disease complexity, and evidence from clinician interviews and surveys that clinicians balance bleeding and ischaemic risk when prescribing DAPT to their patients; and (3) non-adherence to DAPT, which was substantial, and generally higher in the stronger antiplatelet treatment groups. Medication knowledge and understanding, and confidence in dealing with symptoms facilitate positive attitudes towards adherence to DAPT, but may be hindered by opportunities to access relevant, timely and appropriate medication counselling. Although we derived relevant utility decrements for the included population using a patient elicitation exercise, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and valued using general population tariffs, we could not conduct a formal cost-effectiveness analysis given the uncertainty around the estimates for bleeding. Nevertheless, the results using routinely collected data need to be carefully considered by clinicians and decision-makers, given that the increased risk of bleeding we observed with more potent DAPT was not offset by a reduced risk of cardiovascular events and that several recent large meta-analyses of RCTs have also failed to show a conclusive benefit of more potent antiplatelet therapy on cardiovascular events. Future work Future research should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Research is needed to develop guidance for identifying confounders and how confounders should be organised into confounding domains to facilitate consistent implementation of the Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) tool. The principle of designing an observational study to emulate a RCT by first defining a target trial appears to be a robust approach, highlighting where the emulation succeeds or fails. Nevertheless, further research is required to validate instances in which an emulation is considered to have been successful, ideally prospectively (i.e. using observational data to emulate ongoing RCTs before their data are analysed and the results are known).We recommend that our utility decrements are used in future cost-effectiveness analyses of DAPT in a UK setting, particularly for minor bleeding events for which existing evidence is limited. In addition, we recommend that future research focuses on quantifying the value of information from reducing the uncertainty of our estimated utility decrements. This research would demonstrate whether or not conducting a larger, more robust study to collect additional information on the HRQoL impact of minor and major bleeds for patients taking DAPT would be an efficient use of resources. The qualitative study with patients highlighted that medication knowledge and understanding, and confidence in dealing with symptoms, facilitate positive attitudes towards adherence to DAPT, but that, currently, there are limited opportunities for patients to access relevant, timely and appropriate DAPT medication counselling. Future qualitative research should focus on developing an intervention to support service users taking DAPT. Trial registration This trial is registered as ISRCTN76607611. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

The collection of a subset of CFS/ME patient data as part of the.national CFS/ME collaborative was confirmed to be service evaluation by the North Somerset & Bristol Research Ethics Committee under REC reference 07/Q2006/48, and in a letter dated 29 January 2007 the Chair of the Research Ethics Committee had previously confirmed (a) that it would not be necessary to apply for ethical permission to use the data being collected as part of service evaluation for the national CFS/ME collaborative and (b) that if in future this data were to be used as part of a research project, this would be agreeable. The "Ethical Approval" section of this paper has been updated to read The data used in this study was originally collected and collated in the National Outcomes Database for the purposes of evaluation of CFS/ME services. [Extracted from the article]

Appropriate imputation inference requires both an unbiased imputation estimator and an unbiased variance estimator. The commonly used variance estimator, proposed by Rubin, can be biased when the imputation and analysis models are misspecified and/or incompatible. Robins and Wang proposed an alternative approach, which allows for such misspecification and incompatibility, but it is considerably more complex. It is unknown whether in practice Robins and Wang's multiple imputation procedure is an improvement over Rubin's multiple imputation. We conducted a critical review of these two multiple imputation approaches, a re-sampling method called full mechanism bootstrapping and our modified Rubin's multiple imputation procedure via simulations and an application to data. We explored four common scenarios of misspecification and incompatibility. In general, for a moderate sample size (n = 1000), Robins and Wang's multiple imputation produced the narrowest confidence intervals, with acceptable coverage. For a small sample size (n = 100) Rubin's multiple imputation, overall, outperformed the other methods. Full mechanism bootstrapping was inefficient relative to the other methods and required modelling of the missing data mechanism under the missing at random assumption. Our proposed modification showed an improvement over Rubin's multiple imputation in the presence of misspecification. Overall, Rubin's multiple imputation variance estimator can fail in the presence of incompatibility and/or misspecification. For unavoidable incompatibility and/or misspecification, Robins and Wang's multiple imputation could provide more robust inferences. [ABSTRACT FROM AUTHOR]

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, National and international guidelines on antiretroviral therapy for HIV infection recently changed to recommend earlier treatment, following the publication during 2009 of two collaborative analyses of HIV cohort studies [1,2]. [...]

Background: Historical cohort studies in England have found that impaired fetal growth and lower respiratory tract infections in early childhood are associated with lower levels of lung function in late adult life. These relations are investigated in a similar study in Scotland.Methods: In 1985-86 a follow up study was carried out of 1070 children who had been born in St Andrew's from 1921 to 1935 and followed from birth to 14 years of age by the Mackenzie Institute for Medical Research. Recorded information included birth weight and respiratory illnesses. The lung function of 239 of these individuals was measured.Results: There was no association between birth weight and lung function. Pneumonia before two years of age was associated with a difference in mean forced expiratory volume in one second (FEV1) of -0.39 litres (95% confidence interval (CI) -0.67, -0.11; p = 0.007) and in mean forced vital capacity (FVC) of -0.60 litres (95% CI -0.92, -0.28; p < 0.001), after controlling for age, sex, height, smoking, type of spirometer, and other illnesses before two years. Similar reductions were seen in men and women. Bronchitis before two years was associated with smaller deficits in FEV1 and FVC. Asthma or wheeze at two years and older and cough after five years were also associated with a reduction in FEV1.Conclusions: The relation between impaired fetal growth and lower lung function in late adult life seen in previous studies was not confirmed in this cohort. The deficits in FEV1 and FVC associated with pneumonia and bronchitis in the first two years of life are consistent with a causal relation. [ABSTRACT FROM AUTHOR]

Background:Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing.Methods:Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up.Results:Among randomised practices, 271 (68%) in the intervention arm (198 114 men) and 302 (78%) in the control arm (221 929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices).Conclusions:The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening. [ABSTRACT FROM AUTHOR]

Background: Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services. Aim: Investigate the outcome of patients with CFS and what factors predict outcome. Design: Longitudinal patient cohort. Methods: We used data from six CFS/ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8-20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up. Results: Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [mean difference from assessment to outcome: -6.8; 95% confidence interval (CI) -7.4 to -6.2; P < 0.001]; physical function (4.4; 95% CI 3.0-5.8; P < 0.001), anxiety (-0.6; 95% CI -0.9 to -0.3; P < 0.001), depression (-1.6; 95% CI -1.9 to -1.4; P < 0.001) and pain (-5.3; 95% CI -7.0 to -3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up. Conclusions: Patients who attend NHS specialist CFS/ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment. [ABSTRACT FROM AUTHOR]

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: Despite the wealth of research investigating the association of unemployment with suicide in the West, few studies have investigated the association in non-Western countries. This study aimed to investigate the relationship between secular trends in unemployment and suicide in Taiwan. Study design: Time-series analysis. Methods: Overall and age-specific suicide rates (1959-2007) for Taiwanese men and women aged 15 years or above were calculated from national population and mortality statistics. The association of secular trends in unemployment with suicide was investigated graphically and using time-series modelling (Prais-Winsten regression). Results: Rises in unemployment were associated with an increase in male suicide rates, but evidence for an association in females was limited. In the model controlling for changes in gross domestic product (GDP) per capita, GDP growth, divorce and female labour force participation, for every 1% rise in unemployment, male suicide rates increased by 3.1 (95% confidence interval 1.4-4.8) per 100,000. There is no evidence for a difference in the strength of association between men of different ages. Conclusion: Trends in suicide, particularly for adult males, appear to be influenced by unemployment. The results have implications for suicide prevention, in particular for societies facing acute rises in unemployment during recessions. [ABSTRACT FROM AUTHOR]

Background: Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences on the development of asthma and airway diseases in predisposed individuals.Methods: Data collected on wheezing at seven time points from birth to 7 years from 6265 children in a longitudinal birth cohort (the ALSPAC study) were analysed. Latent class analysis was used to assign phenotypes based on patterns of wheezing. Measures of atopy, airway function (forced expiratory volume in 1 s (FEV(1)), mid forced expiratory flow (FEF(25-75))) and bronchial responsiveness were made at 7-9 years of age.Results: Six phenotypes were identified. The strongest associations with atopy and airway responsiveness were found for intermediate onset (18 months) wheezing (OR for atopy 8.36, 95% CI 5.2 to 13.4; mean difference in dose response to methacholine 1.76, 95% CI 1.41 to 2.12 %FEV(1) per mumol, compared with infrequent/never wheeze phenotype). Late onset wheezing (after 42 months) was also associated with atopy (OR 6.6, 95% CI 4.7 to 9.4) and airway responsiveness (mean difference 1.61, 95% CI 1.37 to 1.85 %FEV(1) per mumol). Transient and prolonged early wheeze were not associated with atopy but were weakly associated with increased airway responsiveness and persistent wheeze had intermediate associations with these outcomes.Conclusions: The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months. This has potential implications for the timing of environmental influences on the initiation of atopic wheezing in early childhood. [ABSTRACT FROM AUTHOR]

Periodontal disease has been suggested to be an important risk factor for preterm low birthweight (PLBW). Here we report a case-control study of 236 cases (infants < 37 wks and weighing < 2499 g) and a daily random sample of 507 controls (⩾ 38 wks and weighing ⩾ 2500 g). Clinical periodontal indices were measured on the labor wards. Associated risk factors for periodontal disease and PLBW were ascertained by means of a structured questionnaire and maternity notes. The risk for PLBW decreased with increasing pocket depth (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.68 to 1.00). After adjustment for maternal age, ethnicity, maternal education, smoking, alcohol consumption, infections, and hypertension during pregnancy, this decreased further (OR 0.78, 95% CI 0.64 to 0.99). We found no evidence for an association between PLBW and periodontal disease. Our results do not support a specific drive to improve periodontal health of pregnant women as a means of improving pregnancy outcomes. [ABSTRACT FROM AUTHOR]